Effects of strength training on functional ambulation following knee replacement: a systematic review, meta-analysis, and meta-regression

Strength training is recommended by the American Physical Therapy Association to improve muscle strength, mobility, and balance following knee replacement. Few studies have focused on the direct effects of strength training on functional ambulation, and potential dose–response relationships between strength training parameters and the effect remain unclear. The aim of this systematic review, meta-analysis, and meta-regression was to evaluate the effects of strength training on functional ambulation following knee replacement (KR). We also aimed to explore potential dose–response relationships between strength training parameters and performance in functional ambulation. A systematic literature search of eight online databases was performed on March 12, 2023, for randomized controlled trials evaluating the effects of strength training on functional ambulation by six-minute walk test (6MWT) or timed-up and go test (TUG) after KR. Data were pooled by random-effect meta-analyses and presented as weighted mean difference (WMD). A random-effect meta-regression was performed for four predetermined training parameters, namely, duration (weeks), frequency (sessions per week), volume (time per session), and initial time (after surgery) separately to explore dose–response relationships with WMD. Fourteen trials encompassing 956 participants were included in our study. Meta-analyses showed an improvement in 6MWT performance after strength training (WMD: 32.15, 95% CI 19.44–44.85) and a decrease in time to complete TUG (WMD: − 1.92, 95% CI − 3.43 to − 0.41). Meta-regression revealed a dose–response relationship only between volume and 6MWT, with a decreasing trend (P = 0.019, 95% CI − 1.63 to − 0.20). Increasing trends of improvement in 6MWT and TUG were observed with increasing training duration and frequency. A slight decreasing trend of improvement was observed in 6MWT with postponed initial time, while an opposite trend was observed in TUG. Based on existing studies, moderate-certainty evidence suggests that strength training could increase 6MWT distance, and low-certainty evidence shows that strength training could decrease the time to complete TUG after KR. Meta-regression results only suggested a dose–response relationship between volume and 6MWT with a decreasing trend. Registration: PROSPERO: CRD42022329006.

Eligibility criteria. The eligibility criteria were as follows.
Participants: The patients underwent primary KR due to KOA. Patients with severe comorbidities (such as uncontrolled diabetes and severe cardiovascular or neurological diseases) that could affect functional ambulation performance were excluded.
Intervention: The experimental group received strength training with or without standard care. Strength training was defined as an exercise for increasing muscle power against a force or gravity 12 . A treatment protocol or an added protocol for the intervention group was regarded as a strength training protocol if: (1) the time for strength training constituted more than half of the total training time (the time for warm-up and cool-down exercises was not calculated) and (2) the researchers hypothesized that it could cause larger improvement in muscle strength or functional ambulation than the control treatment, or else augment the improvement of muscle strength or functional ambulation on the basis of the control treatment.
Control: The control group received standard care or no intervention. As the APTA guideline highlights that strength training is beneficial for mobility, balance, and knee extension after KR, and due to ethical concerns, strength training is sometimes included in standard care protocols 10 . In this study, we distinguished standard care protocols from strength training protocols if: (1) strength training was one of the applied therapies (e.g., knee range of motion training, balance training, cryotherapy) in a protocol, (2) the time for strength training constituted no more than half of the total training time, and (3) the aim of the protocol was not to improve muscle strength or functional ambulation specifically. Studies of strength training in both treatment and control groups with different parameters (high intensity vs. low intensity, weight-bearing vs. non-weight-bearing, etc.) were excluded.
Outcome: The 6-min walk test (6MWT) was selected as the primary outcome as it reflects a person's walking distance in 6 min, which is close to situations of daily living. The timed-up and go (TUG) test was selected as the secondary outcome. In this test, participants need to stand up from a seated position, walk 3 m, turn back, and sit down. A decrease in the time needed to complete TUG indicates an improvement in the outcome 13 .
Study: Randomized controlled trials (RCTs) published in English or Chinese were included, with no restrictions in terms of year, region, and ethnicity. Selection process. The retrieved articles were imported into Endnote 20.3, and duplications were removed.
Two independent reviewers read titles and abstracts of all articles, and then a full-text evaluation of potentially eligible articles was performed. The final selection results were cross-checked between the two reviewers, and conflicts were solved by discussion or by consulting a third reviewer.
Data extraction. Information from the eligible studies was extracted by two independent reviewers using a predesigned data extraction form. The following information was collected: (1) study characteristics: publishing year, country or region, first author, and number of participants in each group; (2) patients' baseline characteristics: mean age, body mass index (BMI), and proportion of male/female; (3) strength training characteristics: details of training procedures, duration (weeks), frequency (sessions per week), volume (minutes per session), and initial time (after surgery); (4) outcomes of functional ambulation. Discrepancies were solved by discussion.

Meta-analyses.
We quantified the effects of strength training on functional ambulation by meta-analyses using the random-effect model. Results of continuous variables were expressed as weighted between-group mean difference (WMD) with a 95% confidence interval (CI). For studies with two intervention groups, we divided the control group into two (WMD remained unchanged, while the sample size and the standard deviation halved) 15 . P < 0.05 was considered statistically significant. In addition, we also computed the weighted mean differences within the strength training group from baseline to posttreatment by using random-effect metaanalyses. Inter-study heterogeneity was evaluated by the I 2 statistic test. I 2 values of 20, 50, and 75% indicate that there might be low, moderate, and high heterogeneity, respectively 16 . Publication bias was evaluated via funnel plots if there were 10 or more studies in one meta-analysis. Egger regression test was performed when the funnel plot showed obvious asymmetry, with a P value > 0.1 indicating potential publication bias 17 . Sensitivity analysis was performed by the leave-one-out method to find any influential studies.
Confidence level assessment of meta-analysis results. We used the GRADE tool to evaluate the confidence level of our results in GRADEpro software (version 3.6.1). The results of meta-analyses from RCTs had a high confidence level initially. If there was risk of bias, inconsistency, indirectness, imprecision, and publication bias in the included studies, the confidence level was downgraded to moderate, low, or very low 18 .

Meta-regression.
We determined the following critical strength training parameters that might affect the training effects a priori based on the previous studies: duration (training weeks) 19 , frequency (sessions per week) 19,20 , volume (minutes per session) 21 , and initial time (days after surgery) 22 . For each outcome, randomeffect univariate meta-regressions were performed by residual restricted maximum likelihood method to measure the between-study variance 23 . The dependent variable was WMD, while the parameters were selected as covariates. Multivariate meta-regression with Knapp-Hartung modification was performed if the number of parameters with statistical significance (P < 0.05) was more than one. Permutation tests were performed to deal with multiple testing (n = 1000) 23 . P < 0.05 in the multivariate meta-regression indicated a more convincing dose-response relationship between a parameter and the outcome than that in the univariate meta-regression. The bubble plot was presented for the trend of dose-response relationship. All statistical analyses and metaregression were performed in Stata 17.0 software (StataCorp LLC, College Station, USA).

Results
Search results. A total of 7448 articles were retrieved, and 5170 articles remained after removing duplicates. Twenty-eight studies were full-text evaluated after title and abstract screening. Finally, 14 studies were included in meta-analyses. Fourteen studies were excluded due to the following reasons: (1) authors did not assess participants' functional ambulation 24-27 ; (2) the intervention group received more functional training (e.g., aerobic exercise and balance training) than strength training 28-31 ; (3) both groups received strength training, only with different parameters [32][33][34] ; (4) strength training was applied in the control group, and the intervention group received other treatments 35 ; (5) other reasons, including non-RCT study design or a lack of training parameters 36,37 (Fig. 1).

Characteristics of the included studies. Publication countries of the 14 RCTs included in our study
were Austria (1 study), Korea (1 study), China (4 studies), Norway (1 study), India (1 study), Denmark (2 studies), Canada (1 study), United States of America (1 study), Australia (1 study), and Finland (1 study). A total of 956 participants were included, with the mean age ranging from 61.8 to 73.1 years, and mean BMI ranging from 23.8 to 37.6 kg/m 2 .

Risk of bias in the included studies. As shown in
Eight studies had one or two domains with "some concerns, " so their overall risk was rated as "some concerns.  Table S3 online), but none of its eligibility criteria, baseline characteristics of participants, and treatment protocols in both groups were outlined after reassessing. Besides, the overall point estimate after leaving out Huang's study was still within the 95% CIs. Thus, that study was still included in the meta-regression. The funnel plot was asymmetric, but the Egger test did not show any potential publication bias (p = 0.19) (see Supplementary  TUG . Eight studies encompassing 601 participants presented data for TUG. The point estimates of the included studies were on the same side, except for the study by Bily et al. 43 , which showed that there was a significant 0.6 s lower decrease in time to complete TUG in the strength training group than in the control group. Random-effect meta-analysis showed statistically significant between-group differences (MD: − 1.92, 95% CI − 3.43 to − 0.41, P = 0.012) (Fig. 3). The value of I 2 was 92%, which indicated that there might be heterogeneity between the studies. Sensitivity analysis did not show obvious changes in the effect estimates by the leave-one-out method (see Supplementary Fig. S6 and Table S7 online). The MD within the strength training group from baseline to posttreatment was − 5.4 (95% CI − 7.6 to − 3.1) seconds (see Supplementary Fig. S8 online).

Confidence level of meta-analyses results.
The confidence level of our meta-analyses results was evaluated by the GRADE tool. For 6MWT, the confidence level was downgraded from high to moderate due to inconsistency (moderate-quality evidence), and for TUG, the confidence level was downgraded from high to low due to imprecision and inconsistency. The reasons for downgrading are shown in Supplementary Figs. S9 and S10 online.

Meta-regression results and dose-response relationship.
A univariate meta-regression was performed for the four strength training parameters (duration, frequency, volume, and initial time) separately.

Discussion
In this dose-response meta-analysis, the general effects of strength training on functional ambulation following KR were first evaluated. Then, we explored the dose-response relationships between the four predetermined training parameters and the outcome, which was a critical aspect of rehabilitation following KR.

Effects of strength training on functional ambulation after KR.
Our study found a larger improvement (6MWT: 32 m, TUG: − 1.9 s) in functional ambulation of the strength training group relative to the control Table 2. Risk of bias in the included studies. L low risk of bias, SC some concerns. www.nature.com/scientificreports/ group. As a long-term goal after KR, functional ambulation improvement involves demands for primary goals such as muscle strength restoration, balance control, and pain management 6,50,51 . Hence, our results could, from another point of view, confirm the results of previous studies that adding strength training to rehabilitation protocols after KR could improve these primary goals 24,26,39 . Moreover, this finding could complement the APTA guideline on the benefits of strength training after KR to some extent, in addition to improvement of muscle strength, mobility, balance, and knee extension 10 . www.nature.com/scientificreports/ We also computed the differences between baseline and posttreatment within the strength training group. The results showed 112.4 m increase for 6MWT (the study by Jakobsen et al. 40 was not included because its baseline was preoperative) and − 5.4 s decrease for TUG, both of which reached the minimal detectable change (61.34 m at a 90% confidence level 52 and − 2.27 s at a 95% confidence level 53 , respectively). Potential mechanisms of functional ambulation improvement following strength training might be explained by neuromuscular reactivation. Patients following KR may exhibit quadricep weakness and atrophy resulting from long-term KOA and the surgery, which can further lead to persistent neuromuscular activation deficits 6,54 . Such deficits can limit the ability to generate force and result in poor physical functions 6 . Strength training could cause a series of neurological reactivation at cortical or spinal level, including reduced variability of motor unit discharge rate, decreased motor unit recruitment threshold, increased motor neuron output, and enhanced muscle strength 55-58 . Dose-response relationship between strength training and functional ambulation. Volume. Meta-regression suggested that there was a dose-response relationship between volume and 6MWT result with a decreasing trend. Such results differed both from our hypothesis that the training effect would increase, at least to a certain range, with the increase in training volume, and a previous study that showed similar increases in muscle strength among small and high volumes of strength training 59 . A far-fetched explanation could be that a large training volume could cause pain and muscle fatigue, thereby reducing performance in functional ambulation. However, considering parameters separately was likely to neglect the interactions among them, as basic information for a strength training prescription should contain intensity, frequency, and repetitions in addition to volume 60 . Frequency and duration. Some trends among the training parameters and outcomes were found, though there were no significant dose-response relationships. Improvements were found in both 6MWT (increased meters) and TUG (decreased seconds) with the increases in training duration and frequency. We were not able to explore the combined contributions of these two parameters to the outcome as neither of them had a doseresponse relationship. Some previous studies have suggested that total training time rather than single frequency or duration improves strength 19 . When patients are trained one to three times per week and the total training time is unequaled, the muscle force increase is related to a long duration with higher frequency rather than frequency itself 20 . When the training frequency is three times per week, a longer total training time results in a greater muscle force increase 21 .

Initial time.
A slight decreasing trend of improvement was observed in 6MWT with postponed initial time (ranging from 0 to 423 days after surgery), meaning that early strength training has a higher potential benefit than late strength training. Current evidence suggests that early training, also known as fast-track rehabilitation, can shorten the in-patient stage and alleviate disfunction 61,62 . Neuromuscular activation deficits would persist until training and cause muscle weakness and immobility 54,63,64 . Early strength training activates neuromuscular control shortly after surgery, leading to an increase of 147% and 112% in muscle force and walking speed, respectively, in 2 weeks 22 and preventing further muscle atrophy 58,65 .
A decreasing trend was observed in TUG, suggesting that early strength training had smaller potential benefits than late strength training. This seems to disagree with much of the existing research (mentioned in the last paragraph). The reasons may be that those studies found that earlier strength training was associated with better strength improvement rather than functional ambulation directly.

Limitations and conclusions
There are several limitations to this study: (1) Due to ethical concerns, it is difficult to explore the isolated dose-response relationship between strength training and functional ambulation. We defined training protocols as strength training protocols if time of strengthening exercises constituted more than half of the total training time. Potential selection bias might exist due to subjective judgment of these protocols, though the study selection process was done by two independent reviewers, and discrepancies were finally resolved. (2) Previous studies have confirmed that strength training is not inferior to standard rehabilitation for the improvement of strength and functional ambulation 8,9 . Our results further showed that strength training could improve 6MWT relative to standard care or no treatment. However, only two out of 10 studies showed statistically significant results. Thus, the results of our study should be interpreted with caution, and more studies are warranted for a robust conclusion. (3) Studies in healthy adults have shown that training intensity is a critical parameter for the improvement of muscle strength and functional ability 66,67 . However, insufficient data for this parameter were presented in six included studies, so we were not able to explore the dose-response relationship between it and functional ambulation. In addition, progression is another important parameter during strength training that may affect the outcome, but it is difficult to compare the effects of various progressive designs through meta-regression. The results of this review only represent the mean effect of a period of strength training on functional ambulation in patients after KR. (4) The I 2 statistic test for evaluating heterogeneity in our study depends on sample size but we did not further explore this issue with other tools (e.g., the prediction interval) 68 . (5) We did not search databases for grey literatures (e.g., Google Scholar), which might lead to potential bias in the searching process according to the Risk of Bias in Systematic Reviews (ROBIS) criteria 69 .
In conclusion, though moderate-certainty evidence suggests that strength training could increase 6MWT distance, the result should be interpreted with caution, as only two out of 10 studies showed statistically significant results. Moreover, low-certainty evidence shows that strength training could decrease time to complete TUG after KR. A dose-response relationship was only found between volume and 6MWT (a decreasing trend), which www.nature.com/scientificreports/ is far from the complete picture of relationships between strength training and functional ambulation after KR. More studies with explicit reports of strength training parameters are needed for further exploration of this topic.

Data availability
All data generated or analyzed during this study are included in this published article and its supplementary information files.